This randomized phase II trial studies how well bevacizumab with or without fosbretabulin tromethamine works in treating patients with ovarian epithelial, fallopian tube, or peritoneal cavity cancer that has come back or is persistent. Monoclonal antibodies, such as bevacizumab, find tumor cells and help kill them. Bevacizumab and fosbretabulin tromethamine may stop the growth of ovarian cancer by blocking blood flow to the tumor. It is not yet known whether bevacizumab is more effective with or without fosbretabulin tromethamine in treating ovarian epithelial, fallopian tube, and peritoneal cavity cancer.

Progression-free survival (PFS) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Incidence of adverse events as assessed by CTCAE v 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]

Toxicities will be characterized by their frequency and severity. Differences in the level of toxicities by treatment regimen will be assessed by classifying them as severe or not severe and examining the relative proportion of severe toxicities.

Measurable disease by RECIST criteria and PFS [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Differences between measurable versus non-measurable disease status on PFS and OS will be examined with plots of survival curves, estimates of quartiles and hazard ratios.

Overall survival [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Differences between measurable versus non-measurable disease status on PFS and OS will be examined with plots of survival curves, estimates of quartiles and hazard ratios.

Objective tumor response in patients with measurable disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

The effects of treatment on the proportion responding by RECIST will be examined.

Response by CA-125 [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

The effects of treatment on the proportion responding by CA125 will be examined.

Patients receive bevacizumab IV over 30-90 minutes and fosbretabulin tromethamine IV over 10-20 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab

Given IV

Other Names:

Avastin

rhuMab-VEGF

Drug: Fosbretabulin Tromethamine

Given IV

Other Names:

CA4P

combretastatin A4 phosphate

Zybrestat

Other: Laboratory Biomarker Analysis

Correlative studies

Experimental: Arm II (bevacizumab)

Patients receive bevacizumab as in Arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Biological: Bevacizumab

Given IV

Other Names:

Avastin

rhuMab-VEGF

Other: Laboratory Biomarker Analysis

Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the progression-free survival hazard ratio of the combination of bevacizumab and fosbretabulin tromethamine (CA4P) compared to bevacizumab alone in patients with persistent or recurrent ovarian, fallopian tube, or primary peritoneal cancer.

SECONDARY OBJECTIVES:

I. To determine the nature and degree of toxicity of fosbretabulin tromethamine plus bevacizumab.

III. To determine the overall survival for both regimens. IV. To estimate the proportion of patients with measurable disease who have objective tumor responses by treatment.

V. To provide descriptive information about cancer antigen (CA)-125 responses by regimen and where possible by objective tumor responses.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab IV over 30-90 minutes and fosbretabulin tromethamine IV over 10-20 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive bevacizumab as in Arm I. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Female

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; histologic documentation of the original primary tumor is required via the pathology report

Patients must have measurable disease or detectable (non-measurable) disease:

Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT) scan, magnetic resonance imaging (MRI) or caliper measurement by clinical exam, or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI

Detectable disease in a patient is defined as one who does not have measurable disease but has at least one of the following conditions:

Patients in the measurable disease cohort must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy

Patients must not be eligible for a higher priority Gynecologic Oncology Group (GOG) protocol, if one exists; in general, this would refer to any active GOG phase 3 protocol or rare tumor protocol for the same patient population

Patients who have had one prior treatment must have a performance status of 0, 1, or 2

Patients who have had two or three prior treatments must have a performance status of 0 or 1

Recovery from the effects of recent surgery, radiotherapy, or chemotherapy

Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration

Any other prior therapy directed at the malignant tumor, including chemotherapy, biological/targeted and immunologic agents, must be discontinued at least 3 weeks prior to registration (including small molecules and murine monoclonal antibodies); chimeric or human or humanized monoclonal antibodies (including bevacizumab) or vascular endothelial growth factor (VEGF) receptor fusion protein (including VEGF Trap/aflibercept) must be discontinued for at least 12 weeks prior to registration; no investigational therapy within 30 days prior to the first date of study treatment

Any prior radiation therapy must be discontinued at least 4 weeks prior to registration

Prior therapy:

Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic (biologic/targeted agents, such as bevacizumab) or extended therapy administered after surgical or non-surgical assessment

Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen

Patients are allowed to receive, but are not required to receive, non-cytotoxic (biologic/targeted agents, such as bevacizumab) therapy as part of their primary treatment regimen; patients must have NOT received any non-cytotoxic therapy (biologic/targeted agents) for management of recurrent or persistent disease (e.g., GOG protocol 170 series drugs or bevacizumab)

For the purposes of this study, poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors will be considered "cytotoxic", and prior treatment with PARP inhibitors for primary or recurrent disease WILL be allowed (either alone or in combination with chemotherapy)

Patients with both platinum-sensitive and platinum-resistant disease are eligible; patients with platinum-refractory disease are NOT eligible; platinum-refractory disease is defined as patients who have progression of disease during the preceding platinum treatment

Definitions:

Platinum-free interval (PFI) is the period of time from the date of last platinum therapy to the date of progression (recurrence by CA-125, CT, etc.; CT is preferred) of disease or initiation of subsequent therapy (whichever occurs first); non-platinum maintenance therapy (e.g., extending taxane treatment) is excluded as a "subsequent therapy;" if the patient's last regimen used platinum, and she has NOT progressed before enrolling onto this study, then her PFI will be calculated from the date of last platinum therapy to the date of registration onto this study

PFI for the most recent platinum therapy will need to be calculated before enrollment onto this study for stratification purposes (i.e. balanced randomization)

Patients who have a PFI =< 182 days (26 weeks) are defined as "platinum resistant;" patients who have 182 < PFI =< 365 days are defined as "GOG platinum sensitive;" finally, patients with PFI > 365 days are defined as "platinum sensitive"

ANC greater than or equal to 1,500/mcl

Platelets greater than or equal to 100,000/mcl

Hemoglobin greater than or equal to 9 g/dL

Creatinine less than or equal to 1.5 x institutional upper limit of normal (ULN)

Potassium within the normal reference range for the laboratory; correction with supplements is acceptable

Magnesium within the normal reference range for the laboratory; correction with supplements is acceptable

Calcium within the normal reference range for the laboratory; correction with supplements is acceptable

Prothrombin time (PT) such that international normalized ratio (INR) is less than or equal to 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin) and a partial thromboplastin time (PTT) less than or equal to 1.5 x ULN

Urine protein should be screened by urine analysis; if protein is 2+ or higher, a 24-hour urine protein should be obtained and the level must be < 1,000 mg (< 1.0 g/24 hrs) for patient enrollment

Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing an effective form of contraception

Patients must have signed an approved informed consent and authorization permitting the release of personal health information

Patients must meet pre-entry requirements

Exclusion Criteria:

Patients who have received prior fosbretabulin tromethamine or any other vascular disrupting agent (VDA)

Patients with other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies as noted below, are excluded if there is any evidence of other malignancy being present within the last three years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy

Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease

Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease

Patients with serious non-healing wound, ulcer, or bone fracture; this includes history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 90 days prior to the first date of study treatment

Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels

Patients with history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months prior to the first date of treatment on this study

Requirement for receiving any drug known to prolong the QTc interval, including anti-arrhythmic medications; stable regimen of antidepressants of the selective serotonin reuptake inhibitor (SSRI) class is allowed

Serious cardiac arrhythmia requiring medication; this does not include asymptomatic, atrial fibrillation with controlled ventricular rate

Patients who have received prior treatment with an anthracycline (including doxorubicin and or pegylated liposomal doxorubicin [Doxil; PLD]) must have an echocardiogram assessment and are excluded if they have an ejection fraction < 50%

Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study; the investigator can consult the Study Chair or Study Co-Chairs for uncertainty in this regard

Patients who are pregnant or nursing

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01305213